DESCRIPTION (From the Applicant's Abstract): Our goals are to understand the role(s) of neurotrophins in (i) central nervous system (CNS) neuronal survival, (ii) neuronal differentiation, and (iii) protection against neuronal damage. Neurotrophins are a four-member family of structurally related proteins; Nerve Growth Factor (NGF), Brain Derived Neurotrophic Factor (BDNF), Neurotrophin-3 (NT-3) and Neurotrophin-4 (NT-4). BDNF, NT-3 and NT-4 are potent survival factors for many types of CNS neurons. We derived mice carrying null mutations in individual as well as in two or three neurotrophin genes; e.g., NT-4-/- mice, [BDNF-/-, NT-4-/-] mice, [BDNF-/-, NT-3-/-, NT-4-/-] mice, etc. Using these mice, we can ask questions about neuronal survival and differentiation in vivo that could not previously be posed. We will investigate neurotrophin-dependence for CNS neuronal survival, neuronal differentiation in the hippocampus, and neuronal response to ischemia. Our first aim is to determine whether neurotrophins are essential for the survival of hippocampal neurons during embryonic and postnatal development. Previous studies and our preliminary results suggest that multiple/alternative neurotrophins can deliver the signal for CNS neurons to survive and CNS neurons may depend on neurotrophins to survive during postnatal development. To test these hypotheses, NT-4-/- and [BDNF-/-, NT-3-/-, NT-4-/-] mice will be examined histologically and immunohistologically to determine (i) whether there is excessive CNS neuronal death during (i) embryogenesis, and (ii) postnatal development. Our second aim is to define neurotrophin function in regulating neurite outgrowth in the hippocampus during postnatal development. (i) [BDNF-/-, NT-3-/-, NT-4-/-] mice will be used to determine whether neurotrophins control neurite outgrowth. (ii) mice carrying null mutations in individual neurotrophin genes will be used to determine the specificity of each neurotrophin in neurite outgrowth. (iii) physical exercise will be applied to NT-4-/- and wild type mice to determine whether NT-4 mediate activity-dependent neurite outgrowth. (iv) exogenous NT-4 will be used to rescue the potential abnormal neurite outgrowth. Our third aim is to determine whether neurotrophins play a role(s) in protecting the adult nervous system against injury. Our preliminary results showed that NT-4-/- mice have an increased neuronal loss in ischemia. (i) NT-4 and BDNF expression during ischemia will be examined. (ii) exogenous NT-4 and BDNF will be tested for protective effects in our ischemic model. In vitro experiments suggest that neurotrophins modulate CNS neuronal survival and differentiation. Our neurotrophin knockout mice allow us to determine the roles of the various neurotrophins in vivo.